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Using infant hair to diagnose a rare disease. Essential lipids for a healthy skin barrier. How cardiolipin mediates ADP/ATP carrier modulation. We offer summaries of papers on these topics recently published in the Journal of Lipid Research.

Using infant hair to diagnose a rare disease

Cholesterol is necessary for embryonic development and serves as a precursor of steroid hormones, Vitamin D, the protective lining of neurons, and digestive acids. Smith–Lemli–Opitz syndrome, or SLOS, is a rare autosomal recessive disorder caused by mutation in the gene encoding the enzyme 7-dehydrocholesterol, or 7-DHC, reductase, which is involved in cholesterol biosynthesis.

SLOS affects 1 in 20,000 to 1 in 60,000 babies and is noticeable before or shortly after birth. Symptoms can include microcephaly (small head), polydactyly (extra fingers and toes), syndactyly (fused fingers and toes), slow growth, mild to severe intellectual disability, and immune and endocrine malfunction. SLOS frequently is associated with low plasma cholesterol levels, and clinical diagnosis is based on physical findings and the presence of elevated plasma levels of the cholesterol precursor 7-DHC. No cure for SLOS exists, but early diagnosis and treatment with extra cholesterol can improve symptoms.

In a recently published in the Journal of Lipid Research, Yitao Luo, Chengqiang Zhang and a multi-institutional research team in China describe how they developed a simple method to measure 7-DHC and cholesterol in human hair simultaneously for SLOS diagnosis.

In this study, the researchers completely pulverized infant hair samples, extracted their biochemical components and then conducted microwave-assisted derivation and analysis by gas chromatography–mass spectrometry, or GC-MS. They found that the sensitivity of the GC-MS based analytical method was significantly higher and the linearity range was wider than reported for previously published methods. They validated the new method using authentic neonatal hair samples collected from 14 healthy infants and two infants with syndactyly whom doctors suspected of having SLOS.

The researchers believe that this noninvasive method for simultaneous measurement of two diagnostic biomarkers for SLOS using human hair is likely to be more accurate than conventional methods using plasma or serum whose biochemical composition can fluctuate in response to diet and environment.

Essential lipids for a healthy skin barrier

Omega-O-acylceramides, or ω-O-acylCers, are essential components of the multilayered lipid assemblies and lipid envelope in the outermost layer of epidermis that forms the permeability barrier in mammalian skin. Consequently, changes in ω-O-acylCers levels cause skin abnormalities such as ichthyosis, characterized by dry, scaly skin. The synthesis of ω-O-acylCers via esterification of ω-hydroxyCers with linoleic acid requires a transacylase enzyme, PNPLA1.

In a recent published in the Journal of Lipid Research, Lukáš Opálka of Charles University in the Czech Republic and an international team of researchers studied ultrastructure of skin samples from neonatal mice lacking the Pnpla1 gene and reported disturbed lamellar lipid organization in the outer skin, indicating that linoleate moiety of ω-O-acylCers plays a role in lamellar pairing and lipid assembly.

The researchers also studied the impact of ω-O-acylCers deficiency on the skin barrier’s lipid assembly using models composed of lipid subclasses containing ω-O-acylCers (healthy skin model), ω-hydroxyCers (Pnpla1 gene deletion) or a combination of the two. X-ray diffraction, infrared spectroscopy and permeability studies indicated that, although a medium lamellar phase is formed under favorable conditions, ω-hydroxyCers could not substitute for ω-O-acylCers in imparting barrier properties to the skin. The results of the study suggest that ω-O-acylCer supplementation is a therapeutic option in patients with dysfunctional PNPLA1.

How cardiolipin mediates ADP/ATP carrier modulation

Cardiolipin, or CL, is a unique phospholipid found in the inner mitochondrial membrane. CL helps maintain membrane architecture and regulate the activity of proteins including adenosine diphosphate and triphosphate carrier, or AAC. AAC catalyzes the exchange of ADP and ATP across the membrane by alternating between two conformations: cytosol-open, or ADP-waiting, and matrix-open, or ATP-waiting.

Qiuzi Yi, Shihao Yao and a team of researchers at the Children’s Hospital, Zhejiang University School of Medicine, China, investigated how binding of CL affects structural dynamics of AAC by comparing molecular dynamics simulations on bovine AAC1 in lipid bilayers with and without CLs. The published in the Journal of Lipid Research show that though CL binding does not affect overall stability or structural symmetry of AAC1, the pocket volumes of AAC1 and interactions involved in the matrix-gate network are more heterogeneous in parallel simulations with membranes containing CLs. The simulation results showed that CL is essential to form a strictly conserved arginine-rich stacking structure that can function as a structural switch for modulation.

While the study showed mechanisms of CL-mediated modulation of cytosol-open AAC function, further work on the matrix-open state and transition pathways between conformations may help better understand CL-mediated modulation of AAC function.